Regulation of vascular tone and blood pressure through endothelial mechanosignaling

Abstract

Most endothelial functions are either controlled by direct mechanical forces such as fluid shear stress or by local or blood-borne mediators acting through specific cell surface receptors. The mechanisms and molecular underpinnings of endothelial shear stress sensing are only partially understood. Among the cell surface receptors for chemical mediators, G-protein-coupled receptors (GPCRS) play a central role as they mediate the intracellular effects of a multitude of auto-/paracrine substances such as histamine, thrombin, chemokines, or lysophospholipids. In addition, several receptor systems have been described to be involved in the mechanosignaling of endothelial cells.

　In the past we have mainly concentrated on how laminar flow on endothelial cells induces activation of eNOS and thereby regulates vascular tone It had been described before that a mechanotransducing complex consisting of PECAM-1, VE-cadherin and VEGF receptor 2 is activated by flow and then promotes phosphorylation and activation of eNOS, most likely via PI-3-kinase and Akt. We could show that this mechanism is under the control of the Gq/G11-coupled P2Y2 receptor, which is activated by ATP released in response to laminar flow from endothelial cells. In a subsequent study we were able to identify the mechanosensitive channel Piezo1 as a putative flow sensor which results in endothelial cell activation and ATP release in part through pannexin channels.

　We are currently studying the role of Gs-mediated signaling in flow-induced eNOS activation and vascular tone control. In addition, we are analyzing the role of Piezo1-dependent mechanosensing and mechanotransduction under pathological conditions which go along with disturbed flow as well as in other endothelial functions including transendothelial migration of immune and tumor cells.